- ACRONYMS AND DEFINITIONS
- ACC - American College of Cardiology
- AHA - American Heart Assoc
- ARB - Angiotensin II receptor blocker
- CAD - coronary artery disease
- CVD - cardiovascular disease
- EF - Ejection Fraction
- HFpEF - Heart failure with preserved ejection fraction
- HFrEF - Heart failure with reduced ejection fraction
- NYHA - New York Heart Association heart failure classification
- SBP - systolic blood pressure
- DRUGS IN CLASS
- Entresto® is a combination pill that contains sacubitril and valsartan
- Sacubitril is a neprilysin inhibitor
- Valsartan is an angiotensin II receptor blocker (ARB)
- MECHANISM OF ACTION
- Sacubitril, neprilysin, and natriuretic peptide
- Natriuretic peptides include Atrial Natriuretic Peptide (ANP), B-type Natriuretic Peptide (BNP), and C-type Natriuretic Peptide (CNP)
- ANP is released by the atria of the heart in response to distension
- BNP is released by the ventricles of the heart in response to distension from volume overload. BNP is sometimes referred to as "brain natriuretic peptide" because it was originally identified in pig brain extracts.
- CNP is released by vascular endothelial cells in response to inflammatory mediators
- Natriuretic peptides are metabolized by an enzyme called neprilysin
- Sacubitril inhibits neprilysin and increases blood levels of natriuretic peptides. Neprilysin is also present in other tissues where it has some important actions. See neprilysin in other tissues for a discussion [1]
- Physiological actions of natriuretic peptides include the following:
- Promote renal excretion of fluid and sodium
- Promote myocardial relaxation and inhibit hypertrophy and fibrosis
- Suppress sympathetic outflow in the brain
- Stimulate vasodilation
- Valsartan
- Valsartan is an angiotensin II receptor blocker (ARB)
- ARBs work by decreasing the effects of the renin-angiotensin-aldosterone-system (RAAS)
- Angiotensin promotes fluid and sodium retention, vasoconstriction, sympathetic outflow, and cardiac hypertrophy and fibrosis. ARBs block angiotensin receptors.
- FDA-APPROVED INDICATION
- Adult heart failure
- Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
- Pediatric heart failure
- Entresto is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. Entresto reduces NT-proBNP and is expected to improve cardiovascular outcomes.
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- The effects of Entresto on heart failure with reduced ejection fraction were evaluated in the PARADIGM-HF trial detailed below. A second study that looked at starting Entresto after an MI in patients with signs of heart failure is also reviewed.
- The PARADIGM-HF study enrolled 8442 patients with NYHA class II - IV heart failure and an ejection fraction ≤ 40%
Main inclusion criteria
- NYHA class II - IV heart failure
- Ejection fraction ≤ 40%
- BNP level ≥ 150 pg/ml or, if they had been hospitalized for heart failure within the previous 12 months, a BNP ≥ 100 pg/ml
Main exclusion criteria
- SBP < 95 mmHg
- CrCl < 30 ml/min
- Potassium > 5.4 mmol/L
- History of angioedema or unacceptable side effect with ACE or ARB
Baseline characteristics
- Average age 64 years
- Average SBP - 122 mmHg
- Average ejection fraction - 29.5%
- Median BNP - 253 pg/ml
- NYHA class: I - 4.6% | II - 70% | III - 24% | IV - 0.7%
- Concomitant meds: Beta blocker - 93% | Aldosterone antagonist - 55% | Diuretic - 80%
Randomized treatment groups
- Group 1 (4187 patients) - Sacubitril 97 mg/Valsartan 103 mg mg twice a day
- Group 2 (4212 patients) - Enalapril 10 mg twice a day
- Before randomization, the trial had two run-in periods where patients who could not tolerate enalapril followed by Entresto were excluded. Most common reasons for exclusion were renal dysfunction, hypotension, and hyperkalemia.
Primary outcome: Composite of death from cardiovascular causes or a first hospitalization for heart failure
Results
Duration: After a median follow-up of 27 months, the trial was stopped early because of clear superiority of Entresto | |||
Outcome | Valsartan-Sacubitril | Enalapril | Comparisons |
---|---|---|---|
Primary outcome | 21.8% | 26.5% | HR 0.80, 95%CI [0.73 – 0.87], p<0.001 |
Death from cardiovascular causes | 13.3% | 16.5% | HR 0.80, 95%CI [0.71 – 0.89], p<0.001 |
First hospitalization for heart failure | 12.8% | 15.6% | HR 0.79, 95%CI [0.71 – 0.89], p<0.001 |
Overall mortality | 17% | 19.8% | HR 0.84, 95%CI [0.76 – 0.93], p<0.001 |
Hypotension | 14% | 9.2% | p<0.001 |
Serum creatinine ≥ 2.5 mg/dl | 3.3% | 4.5% | p=0.007 |
Potassium > 5.5 mmol/L | 16.1% | 17.3% | p=0.15 |
Cough | 11.3% | 14.3% | p<0.001 |
Angioedema | 19 events | 10 events | N/A |
|
Findings: Entresto was superior to enalapril in reducing the risks of death and of hospitalization for heart failure
- STUDY
- Design: Randomized, controlled trial (N=5661 | length = median 22 months) in patients with an MI within the last 7 days accompanied by reduced EF (≤ 40%), pulmonary congestion, or both
- Treatment: Sacubitril–valsartan 97/103 mg twice daily vs Ramipril 5 mg twice daily. Treatment was double-blind.
- Primary outcome: Death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first
- Results:
- Primary outcome: Sacubitril–valsartan - 11.9%, Ramipril - 13.2% (p=0.17)
- Overall mortality: Sacubitril–valsartan - 7.5%, Ramipril - 8.5% (HR 0.88, 95%CI [0.73 - 1.05])
- Findings: Sacubitril–valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction.
- AHA recommendations
- Summary
- In the PARADIGM-HF study, Entresto was clearly superior to enalapril for a number of outcomes. This led to Entresto becoming the preferred first-line treatment for patients with HFrEF.
- In the PARADISE-MI trial, starting Entresto right after an MI that was accompanied by signs of heart failure was not superior to ramipril. The outcomes did show a trend towards superiority with Entresto, but they did not reach statistical significance. This likely occurred because many patients have spontaneous improvement in their EF after MI, and the benefits of Entresto are reduced in this population.
- HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
- Overview
- The effects of Entresto in heart failure with preserved ejection fraction were evaluated in the PARAGON-HF trial detailed below
- The PARAGON-HF trial enrolled 4822 patients with NYHA class II - IV heart failure and an ejection fraction ≥ 45%
Main inclusion criteria
- Age ≥ 50 years
- NYHA class II - IV heart failure
- Ejection fraction ≥ 45%
- Elevated NT-proBNP
- Structural heart disease (LA enlargement or LVH)
- Current treatment with diuretic
Main exclusion criteria
- Any prior ECHO with EF < 40%
- ACS within 3 months
- Current decompensated CHF
- History of angioedema
- Uncontrolled hypertension
Baseline characteristics
- Average age 73 years
- Average EF - 58%
- Atrial fibrillation/flutter - 32%
- History of MI - 22%
- NYHA class: I - 2.8% | II - 77% | III - 20% | IV - 0.4%
Randomized treatment groups
- Group 1 (2407 patients): Sacubitril-Valsartan 97/103 mg twice daily
- Group 2 (2389 patients): Valsartan 160 mg twice daily
- The trial had a run-in phase where patients received valsartan at half the target dose, followed by sacubitril– valsartan at half the target dose. Participants who had no unacceptable side effects in both run-in phases and whose laboratory values remained within prespecified safety criteria underwent randomization
- Renin–angiotensin system inhibitors other than mineralocorticoid-receptor antagonists were discontinued before the run-in period, but all other background medications were continued
- Study drugs were adjusted down if side effects occurred
Primary outcome: Composite of total (first and recurrent) hospitalizations for heart failure and death from cardiovascular causes
Results
Duration: Median of 35 months | |||
Outcome | Sacubitril-Valsartan | Valsartan | Comparisons |
---|---|---|---|
Primary outcome (%/year) | 12.8% | 14.6% | RR 0.87, 95%CI [0.75 - 1.01], p=0.06 |
Hospitalization for heart failure | 690 events | 797 events | RR 0.85, 95%CI [0.72 – 1.00] |
Death from CVD | 8.5% | 8.9% | HR 0.95, 95%CI [0.79 – 1.16] |
Overall mortality | 14.2% | 14.6% | HR 0.97, 95%CI [0.84 – 1.13] |
Hypotension (SBP < 100) | 15.8% | 10.8% | p<0.001 |
Serum creatinine ≥ 2.0 mg/dl | 10.8% | 13.7% | p=0.002 |
Hyperkalemia > 5.5 mEq/L | 13.2% | 15.3% | p=0.048 |
Angioedema | 14 cases | 4 cases | N/A |
Achieved target dose at end of trial | 82% | 85.1% | N/A |
Findings: Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations
for heart failure and death from cardiovascular causes among patients with heart failure
and an ejection fraction of 45% or higher
- Professional recommendations
- Summary
- In the PARAGON-HF trial, Entresto did not achieve its primary outcome, but there was a trend toward a significant decrease in heart failure hospitalizations. Another study (N=2572) that looked at the effect of Entresto on surrogate endpoints in HFpEF found that Entresto lowered NT-proBNP levels but did not improve 6-minute walk distance. [PMID 34783839]
- HFpEF is a difficult condition to treat, and drugs that have been shown to improve HFrEF outcomes have generally fallen flat in HFpEF trials. Based on the available evidence, it's conceivable that some patients with HFpEF may see a small benefit with Entresto.
- SIDE EFFECTS
- Hypotension
- In trials, hypotension was the most commonly reported adverse event with Entresto
- In the PARADIGM-HF trial, hypotension was reported in 18% of Entresto-treated patients and 12% of enalapril-treated patients. In the PARAGON-HF trial, hypotension occurred in 15.8% of Entresto-treated patients and 10.8% of valsartan-treated patients.
- Dose adjustment of Entresto and/or other antihypertensives may be required in some patients [3]
- Hyperkalemia
- Valsartan is an ARB. ARBs may raise potassium levels (see ARBs and hyperkalemia for more). [3]
- Increased serum creatinine
- Valsartan is an ARB. ARBs may raise creatinine levels (see ARBs and serum creatinine for more).
- Angioedema
- Angioedema is an allergic reaction that causes swelling of the face and lips. In severe cases, the tongue and larynx may also swell. The risk of angioedema is higher in black patients.
- ACE inhibitors are known to cause angioedema and ARBs have also been associated with angioedema but to a lesser degree. Sacubitril also appears to increase the risk of angioedema. Entresto should not be taken within 36 hours of an ACE inhibitor. Patients with a history of hereditary angioedema or angioedema induced by an ACE inhibitor or ARB should not take Entresto.
- In the PARADIGM-HF trial, angioedema was reported in 0.5% of Entresto-treated patients and 0.2% of enalapril-treated patients. Among black patients, 2.4% of Entresto-treated patients experienced angioedema compared to 0.5% of enalapril-treated patients.
- In the PARAGON-HF trial, there were 14 cases of angioedema in the Entresto group compared to 4 cases in the valsartan group
- Antihistamines may help relieve mild angioedema. Severe cases involving the tongue and larynx require airway management and medical treatment (e.g., subcutaneous epinephrine/adrenaline solution 1:1000, 0.3 mL to 0.5 mL).
- If angioedema occurs while taking Entresto, it should be discontinued and never restarted [3]
- CONTRAINDICATIONS
- History of ACE inhibitor- or ARB-induced angioedema
- Hereditary angioedema
- Concomitant ACE inhibitors. Do not administer Entresto within 36 hours of an ACE inhibitor.
- Concomitant aliskiren in patients with diabetes
- Hypersensitivity reaction
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 30 ml/min - no dose adjustment necessary
- CrCl < 30 ml/min - recommended starting dose is 24/26 mg twice a day. Double dose every 2 - 4 weeks as tolerated.
- Liver disease
- Mild (Child-Pugh A) - no dose adjustment necessary
- Moderate (Child-Pugh B) - recommended starting dose is 24/26 mg twice a day
- Severe (Child-Pugh C) - not recommended
- Pregnancy
- May cause fetal harm. Only use if drug is considered life-saving for the mother. [3]
- NEPRILYSIN IN OTHER TISSUES
- Brain
- Neprilysin is present in the brain where it plays an important role in the degradation and removal of beta-amyloid
- Beta-amyloid and the plaques that it forms are a key component in the pathogenesis of Alzheimer's disease
- In theory, neprilysin inhibition by sacubitril could lead to increased levels of beta-amyloid in the brain and subsequently increase the risk of Alzheimer's disease
- A study in healthy volunteers found that 194 mg of sacubitril once daily for two weeks raised levels of beta-amyloid in the cerebrospinal fluid (CSF) when compared to placebo
- In the PARADIGM-HF study, Entresto was not associated with an increased risk of memory or cognitive disorders, but the study was too short (median 27 months) to assess the long-term risk of Alzheimer's disease
- The FDA has instructed the manufacturer of Entresto to conduct a long-term study on the effects of the drug on memory and cognitive function. The results of the study will not be available until 2022. [3,4]
- Eye
- Neprilysin is present in the eye where it plays a role in the degradation and removal of beta-amyloid
- Studies suggest that the accumulation of beta-amyloid in the eye may contribute to age-related macular degeneration
- In theory, neprilysin inhibition by sacubitril could lead to increased levels of beta-amyloid in the eye and subsequently increase the risk of macular degeneration
- In murine studies, loss of neprilysin has been shown to cause changes in the eye that are similar to those seen in humans with age-related macular degeneration [4]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Entresto
- ACE inhibitors - DO NOT COMBINE Entresto with an ACE inhibitor. Do not take Entresto within 36 hours of an ACE inhibitor.
- Aliskiren - DO NOT COMBINE Entresto with aliskiren in patients with diabetes or a CrCl < 60 ml/min
- ARBs - Entresto contains the ARB valsartan. It should not be combined with other ARBs.
- Lithium - ARBs can increase lithium levels. This combination should be avoided, or lithium levels should be checked frequently if they are taken together.
- Medications that may raise potassium - use caution when combining with drugs that may raise potassium levels
- Common medications that may raise potassium levels include:
- ACE Inhibitors (lisinopril, benazepril, etc.)
- Aldosterone antagonists (spironolactone, eplerenone)
- Aliskiren (Tekturna®)
- Cyclosporine (Neoral®)
- ENaC inhibitors (triamterene, amiloride)
- Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
- Potassium supplements (K-Dur®, etc)
- Tacrolimus
- Trimethoprim (part of Bactrim® and Septra®)
- Heparin - heparin raises potassium secondarily by inhibiting aldosterone synthesis. LMWH does not appear to have the same effect. [42]
- NSAIDS (Advil®, Aleve®, ibuprofen, naprosyn, Celebrex® etc.) - NSAIDS can attenuate the effect of ARBs. This is more of a concern when NSAIDS are taken on a chronic basis. Cases of decreased kidney function have been reported when NSAIDS were taken with ARBs. The risk appears to be greater with advanced age, dehydration, and underlying kidney disease.
- Potassium supplements (K-Dur®, etc.) - potassium supplements may increase the risk of hyperkalemia when taken with Entresto. Use caution.
- Salt substitutes (No-Salt®, etc.) - salt substitutes typically contain a high amount of potassium (16.4 mEq per 1/4 tsp). Use caution when combining with Entresto.
- Metabolism and clearance
- Sacubitril
- OATP1B1/OATP1B3 - inhibitor
- Valsartan
- OATP1B1/OATP1B3 - substrate
- DOSING
- Dosage forms
- Sacubitril : Valsartan (tablet)
- 24 mg/26 mg
- 49 mg/51 mg
- 97 mg/103 mg
- NOTE: According to the manufacturer, the valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations. Valsartan doses of 26 mg, 51 mg, and 103 mg in Entresto are equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other tablet formulations, respectively.
- Dosing (adults)
- Patients currently taking an ACE or ARB at standard doses✝
- Starting: 49/51 mg twice a day
- Target: 97/103 mg twice a day
- May take without regard to food
- Double starting dose after 2 - 4 weeks to reach target dose
- Allow 36 hours to pass after the last dose of an ACE inhibitor before starting Entresto
- ✝The ACC heart failure guidelines define standard doses of ACE inhibitors as being the equivalent of enalapril ≥ 10 mg twice daily and standard doses of ARBs as being the equivalent of valsartan ≥ 80 mg twice daily [7]
- Patients not currently taking an ACE or ARB or previously taking low doses of these agents✝
- Starting: 24/26 mg twice a day
- Target: 97/103 mg twice a day
- May take without regard to food
- Double dose every 2 - 4 weeks to reach target dose
- Allow 36 hours to pass after the last dose of an ACE inhibitor before starting Entresto
- ✝The ACC heart failure guidelines define low doses of ACE inhibitors as being the equivalent of enalapril < 10 mg twice daily and low doses of ARBs as being the equivalent of valsartan < 80 mg twice daily [7]
- Elderly (≥ 75 years)
- The ACC heart failure guidelines recommend a starting dose of 24/26 mg in elderly patients [7]
- May take without regard to food
- Dosing (≥ 1 year old)
- Doses for pediatric patients are provided in the table below. Doses are given twice daily. Dose should be titrated every 2 weeks as tolerated.
Titration Step Dose (twice daily) | |||
---|---|---|---|
Starting | Second | Final | |
< 88 lbs (40 kg)✝ | 1.6 mg/kg | 2.3 mg/kg | 3.1 mg/kg |
88 lbs (40 kg) to 109 lbs (50 kg) | 24/26 mg | 49/51 mg | 72/78 mg‡ |
≥ 110 lbs (50 kg) | 49/51 mg | 72/78 mg‡ | 97/103 mg |
- LONG-TERM SAFETY
- Valsartan was FDA-approved in 2001. It has been shown to be safe with long-term use.
- Sacubitril was FDA-approved in 2015. It has no long-term safety data.
- There are some significant concerns about the theoretical long-term adverse effects of sacubitril. See neprilysin in other tissues for more.
- BIBLIOGRAPHY
- 1 - PMID 25213572 - NP review
- 2 - PMID 25176015 - Paradigm-HF study
- 3 - Entresto PI
- 4 - PMID 26641736 - Neprilysin and Alzheimer's disease
- 5 - PMID 27208050 - PMID 2016 AHA HF update
- 6 - PMID 28455343 - PMID 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
- 7 - PMID 29277252 - PMID 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction, J Am Coll Cardiol (2018)